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Acute intermittent hypoxia drives hepatic lipogenesis in humans and rodents.
No full textBackground and aims
Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition. It is tightly associated with an adverse metabolic phenotype (including obesity and type 2 diabetes) as well as with obstructive sleep apnoea (OSA) of which intermittent hypoxia is a critical component. Hepatic (DNL) is a significant contributor to hepatic lipid content and the pathogenesis of NAFLD and has been proposed as a key pathway to target in the development of pharmacotherapies to treat NAFLD. Our aim is to use experimental models to investigate the impact of hypoxia on hepatic lipid metabolism independent of obesity and metabolic disease.
Methods
Human and rodent studies incorporating stable isotopes and hyperinsulinaemic euglycaemic clamp studies were performed to assess the regulation of DNL and broader metabolic phenotype by intermittent hypoxia. Cell-based studies, including pharmacological and genetic manipulation of hypoxia-inducible factors (HIF), were used to examine the underlying mechanisms.
Results
Hepatic DNL increased in response to acute intermittent hypoxia in humans, without alteration in glucose production or disposal. These observations were endorsed in a prolonged model of intermittent hypoxia in rodents using stable isotopic assessment of lipid metabolism. Changes in DNL were paralleled by increases in hepatic gene expression of acetyl CoA carboxylase 1 and fatty acid synthase. In human hepatoma cell lines, hypoxia increased both DNL and fatty acid uptake through HIF-1α and -2α dependent mechanisms.
Conclusions
These studies provide robust evidence linking intermittent hypoxia and the regulation of DNL in both acute and sustained models of intermittent hypoxia, providing an important mechanistic link between hypoxia and NAFLD
Treatment of anastomotic leak after esophagectomy: insights of an international case vignette survey and expert discussions.
No full textAnastomotic leak (AL) is a severe complication after esophagectomy. Clinical presentation of AL is diverse and there is large practice variation regarding treatment of AL. This study aimed to explore different AL treatment strategies and their underlying rationale. This mixed-methods study consisted of an international survey among upper gastro-intestinal (GI) surgeons and focus groups with expert upper GI surgeons. The survey included 10 case vignettes and data sources were integrated after separate analysis. The survey was completed by 188 respondents (completion rate 69%) and 6 focus groups were conducted with 20 international experts. Prevention of mortality was the most important goal of primary treatment. Goals of secondary treatment were to promote tissue healing, return to oral feeding and safe hospital discharge. There was substantial variation in the preferred treatment principles (e.g. drainage or defect closure) and modalities (e.g. stent or endoVAC) within different presentations of AL. Patients with local symptoms were treated by supportive means only or by non-surgical drainage and/or defect closure. Drainage was routinely performed in patients with intrathoracic collections and often combined with defect closure. Patients with conduit necrosis were predominantly treated by resection and reconstruction of the anastomosis or by esophageal diversion. This mixed-methods study shows that overall treatment strategies for AL are determined by vitality of the conduit and presence of intrathoracic collections. There is large variation in preferred treatment principles and modalities. Future research may investigate optimal treatment for specific AL presentations and aim to develop consensus-based treatment guidelines for AL after esophagectomy
Interindividual variability in transgene mRNA and protein production following adeno-associated virus gene therapy for hemophilia A.
No full textFactor VIII gene transfer with a single intravenous infusion of valoctocogene roxaparvovec (AAV5-hFVIII-SQ) has demonstrated clinical benefits lasting 5 years to date in people with severe hemophilia A. Molecular mechanisms underlying sustained AAV5-hFVIII-SQ-derived FVIII expression have not been studied in humans. In a substudy of the phase 1/2 clinical trial ( NCT02576795 ), liver biopsy samples were collected 2.6-4.1 years after gene transfer from five participants. Primary objectives were to examine effects on liver histopathology, determine the transduction pattern and percentage of hepatocytes transduced with AAV5-hFVIII-SQ genomes, characterize and quantify episomal forms of vector DNA and quantify transgene expression (hFVIII-SQ RNA and hFVIII-SQ protein). Histopathology revealed no dysplasia, architectural distortion, fibrosis or chronic inflammation, and no endoplasmic reticulum stress was detected in hepatocytes expressing hFVIII-SQ protein. Hepatocytes stained positive for vector genomes, showing a trend for more cells transduced with higher doses. Molecular analysis demonstrated the presence of full-length, inverted terminal repeat-fused, circular episomal genomes, which are associated with long-term expression. Interindividual differences in transgene expression were noted despite similar successful transduction, possibly influenced by host-mediated post-transduction mechanisms of vector transcription, hFVIII-SQ protein translation and secretion. Overall, these results demonstrate persistent episomal vector structures following AAV5-hFVIII-SQ administration and begin to elucidate potential mechanisms mediating interindividual variability
Infection Risk in Sexual Contacts of Syphilis: A Systematic Review and Meta-analysis.
No full textOBJECTIVES
Current guidelines recommend offering epidemiological treatment to asymptomatic contacts of early syphilis. This is on the expectation that up to 60% of sexual contacts of patients with syphilis will be infected. However, the evidence for this figure is sparse. We performed a systematic review and meta-analysis, to estimate the proportion of sexual contacts of syphilis that are infected with syphilis.
METHODS
Two electronic databases (Medline and Embase) were reviewed in March 2021, to identify studies that reported rates of infection in sexual contacts of syphilis.
RESULTS
Of 3,051 Embase and 1,828 Medline articles identified, 32 were included in the meta-analysis. In total 36,397 contacts were tested. The proportion of contacts infected varied across the studies, ranging from 10.7% to 97.5%, resulting in considerable heterogeneity (I=98.5%). Pooling the studies gave an estimated proportion of infected contacts of 32.6% (95% confidence interval: 26.2% - 39.7%).
CONCLUSIONS
The risk of infection in sexual contacts of syphilis reported in the literature is highly variable, with a pooled estimate of 32.6%. This will help guide decisions regarding epidemiological treatment of sexual contacts of patients with syphilis. These decisions are increasingly important in this era of antibiotic resistance, with increasing emphasis being placed on antimicrobial stewardship
Anatomical and audiological considerations in branchiootorenal syndrome: A systematic review.
No full textObjective
Establish anatomical considerations, audiological outcomes, and optimal management in patients with branchiootic/branchiootorenal syndrome (BO/BOR).
Methods
Databases reviewed: Medline, Pubmed, Embase, Web of Science, Cochrane Collection, and ClinicalTrials.gov. Clinical or radiological studies of patients with BOR syndrome describing either the audiological profile or anatomical changes were included. Articles in which BOR syndrome was associated with other syndromes, and those that were focused only on general and genetic aspects of BOR syndrome were excluded. Articles were assessed using Oxford Centre for Evidence-Based Medicine (OCEBM) grading system and the Brazzelli risk of bias tool for nonrandomized studies.
Results
Searches identified 379 articles. Of these, 64 studies met the inclusion criteria, reporting outcomes in 482 patients from at least 95 families. In 308 patients, hearing loss was categorized as sensorineural (29%), conductive (20%), and mixed (51%). Hearing outcomes were variable in terms of onset, pattern, and severity; ranging from mild to profound deafness. One hundred sixty-nine patients presented with inner ear anomalies, 145 had middle, and 151 had external ear abnormalities. In 44 studies, 58 ear operations were described. Mixed outcomes were reported in patients managed with hearing aids or middle ear surgery; however, successful cochlear implantation was described in all five cases.
Conclusion
The anatomical and audiological profiles of patients with BO/BOR are variable. A range of surgical procedures were described, however lacked objective outcome measures. Given the range of anatomical variants, management decisions should be made on an individual basis including full audiological and radiological assessment.
Level of evidence
NA
Correspondence on "Association between occupational exposure to irritant agents and a distinct asthma endotype in adults" by Andrianjafimasy et al.
No full textAngiotensin-converting enzyme inhibitors and risk of age-related macular degeneration in individuals with hypertension.
No full textAIM
Several observational studies have examined the potential protective effect of angiotensin-converting enzyme inhibitor (ACE-I) use on the risk of age-related macular degeneration (AMD) and have reported contradictory results owing to confounding and time-related biases. We aimed to assess the risk of AMD in a base cohort of patients aged 40 and above with hypertension among new users of ACE-I compared to an active comparator cohort of new users of calcium channel blockers (CCB) using data obtained from IQVIA Medical Research database, a primary care database in the UK.
METHODS
In this study, 53,832 and 43,106 new users of ACE-I and CCB were included between 1995 and 2019, respectively. In an on-treatment analysis, patients were followed up from the time of index drug initiation to the date of AMD diagnosis, loss to follow-up, discontinuation or switch to the comparator drug. A comprehensive range of covariates were used to estimate propensity scores to weight and match new users of ACE-I and CCB. Standardized mortality ratio (SMR) weighted Cox proportional hazards model was used to estimate hazard ratios (HRs) of developing AMD.
RESULTS
During a median follow-up of 2 years (interquartile range 1-5 years), the incidence rate of AMD was 2.4 (95% CI 2.2-2.6) and 2.2 (2.0-2.4) per 1,000 person-years among the weighted new users of ACE-I and CCB, respectively. There was no association of ACE-I use on the risk of AMD compared to CCB use in either the propensity score weighted or matched, on-treatment analysis (aHR: 1.07 (95% CI 0.90-1.27) and 0.87 (0.71-1.07) respectively).
CONCLUSION
We found no evidence that the use of ACE-I is associated with risk of AMD in patients with hypertension
Immunofibroblasts regulate LTα3 expression in tertiary lymphoid structures in a pathway dependent on ICOS/ICOSL interaction.
No full textImmunofibroblasts have been described within tertiary lymphoid structures (TLS) that regulate lymphocyte aggregation at sites of chronic inflammation. Here we report, for the first time, an immunoregulatory property of this population, dependent on inducible T-cell co-stimulator ligand and its ligand (ICOS/ICOS-L). During inflammation, immunofibroblasts, alongside other antigen presenting cells, like dendritic cells (DCs), upregulate ICOSL, binding incoming ICOS + T cells and inducing LTα3 production that, in turn, drives the chemokine production required for TLS assembly via TNFRI/II engagement. Pharmacological or genetic blocking of ICOS/ICOS-L interaction results in defective LTα expression, abrogating both lymphoid chemokine production and TLS formation. These data provide evidence of a previously unknown function for ICOSL-ICOS interaction, unveil a novel immunomodulatory function for immunofibroblasts, and reveal a key regulatory function of LTα3, both as biomarker of TLS establishment and as first driver of TLS formation and maintenance in mice and humans
Cost-Effectiveness of iGlarLixi Versus Premix BIAsp 30 in Patients with Type 2 Diabetes Suboptimally Controlled by Basal Insulin in the UK.
No full textINTRODUCTION
iGlarLixi is indicated as an adjunct to diet and exercise in addition to metformin (with or without sodium-glucose cotransporter-2 inhibitors) to improve glycemic control in adults with insufficiently controlled type 2 diabetes (T2D). A cost-effectiveness analysis was conducted to compare iGlarLixi with premix biphasic insulin aspart 30 (BIAsp 30) in people with T2D suboptimally controlled with basal insulin (BI).
METHODS
The IQVIA CORE Diabetes Model was used to estimate lifetime costs and outcomes for people with T2D from a UK health care perspective at a willingness-to-pay threshold of £20,000. Initial clinical data were based on the phase 3 randomized, open-label, active-controlled SoliMix clinical trial which compared the efficacy and safety of once-daily iGlarLixi with that of twice-daily BIAsp 30. Costs associated with management and complications and utilities values were derived from published sources. Lifetime costs (in £GBP) and quality-adjusted life-years (QALYs) were predicted; extensive scenario and sensitivity analyses were conducted.
RESULTS
Estimated QALYs gained were slightly higher with iGlarLixi (8.9 vs. 8.8) compared with premix BIAsp 30, at a higher cost (£23,204 vs. £21,961). The base case incremental cost-effectiveness ratio (ICER) per QALY was £13,598. Treatment acquisition was the main driver of cost differences (iGlarLixi, £11,750; premix BIAsp 30, £10,395). Costs associated with management and complications were generally similar between comparators.
CONCLUSION
iGlarLixi provides improved QALY outcomes at an acceptable cost compared with premix BIAsp 30, with an ICER below the threshold generally considered acceptable by UK authorities. In people with T2D, iGlarLixi is a simple, cost-effective option for advancing therapy of BI, with fewer daily injections than premix BIAsp 30
Exploring the association between self-compassion, mindfulness and mindful eating with eating behaviours amongst patients with obesity.
No full textPeople who have obesity often experience problematic eating behaviours, contributing towards their excessive weight gain. Understanding problematic eating behaviours and their association to self-compassion, mindfulness and mindful eating is important for the development of future interventions that improve weight-loss and weight-regulation. One hundred and one participants attending their first session of a 6-session dietetic programme within a Tier 3 medical weight management service in the West Midlands, UK were recruited to complete questionnaires on self-compassion, mindfulness, mindful eating and eating behaviours, such as, emotional, restrained, external, fat and sugar consumption and grazing. The findings suggested all three constructs, self-compassion, mindfulness and mindful eating were significantly and negatively associated with grazing and emotional eating, but mindful eating was the only construct that also displayed a significant and negative association with other eating behaviours that are often barriers to successful weight regulation, such as external eating and fat consumption. Further investigation suggested mindful eating had an indirect effect on fat consumption and grazing via external eating. Whilst, self-compassion, mindfulness and mindful eating displayed a negative relationship with grazing and emotional eating, mindful eating also displayed a negative relationship with fat consumption and external eating. Possible explanations and directions for future work are discussed with an emphasis on the need for more empirical work